Tofacitinibe, um inibidor de JAK, atenua a inflamação e a perda da integridade epitelial em modelo de colite por TNBS em ratos

Abstract

Introduction: IBDs can be triggered by disturbances in the integrity of the intestinal mucosa, leading to bacterial transmigration. It is essential that the treatment of IBD aims not only to reduce inflammation, but also to reduce the damage to the mucosal barrier function. Inhibition of Janus kinases (JAK) has been targeted for the treatment of inflammatory diseases, including ulcerative colitis. However, little is known about the ability of this class of drugs to reduce the loss of mucosal integrity. Aim: The present study aimed to evaluate the effect of tofacitinib, a JAK pathway inhibitor, on the inflammation and integrity of the colonic mucosa in a TNBS-induced colitis model in rats. Methodology: Colitis was induced in Wistar rats by rectal administration of TNBS (20 mg + 50% ethanol). The control group received only saline solution. Animals were pretreated with tofacitinib (15 mg/kg) or saline 30 minutes before induction and twice daily. After 7 days of induction, the animals were euthanized, the colon removed and myeloperoxidase activity, baseline transepithelial electrical resistance (TER), TER after 1h and fluorescein permeability were evaluated. In addition, RT-PCR and Western Blotting for colon tight junctions (ZO-1, Occludin, Claudin-2, Claudin-15 and Tricellulin). Results: Treatment with tofacitinib significantly reduced (p<0.05) the evaluated inflammatory parameters. In addition, it preserved the integrity of the intestinal epithelial barrier when compared to the colitis group (p<0.05), increasing basal TER levels, reducing TER drop after 1 hour and paracellular permeability to fluorescein, by increasing the relative expression of Occludin and reduction of expression of Claudin-2 and Claudin-15. Conclusion: We conclude that JAK inhibition by tofacitinib was able to reduce not only the inflammatory process, but also the loss of mucosal integrity in an experimental colitis model.